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Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer

Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previ...

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Autores principales: Fan, Li-Ching, Teng, Hao-Wei, Shiau, Chung-Wai, Tai, Wei-Tien, Hung, Man-Hsin, Yang, Shung-Haur, Jiang, Jeng-Kai, Chen, Kuen-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325431/
https://www.ncbi.nlm.nih.gov/pubmed/27580057
http://dx.doi.org/10.18632/oncotarget.11636
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author Fan, Li-Ching
Teng, Hao-Wei
Shiau, Chung-Wai
Tai, Wei-Tien
Hung, Man-Hsin
Yang, Shung-Haur
Jiang, Jeng-Kai
Chen, Kuen-Feng
author_facet Fan, Li-Ching
Teng, Hao-Wei
Shiau, Chung-Wai
Tai, Wei-Tien
Hung, Man-Hsin
Yang, Shung-Haur
Jiang, Jeng-Kai
Chen, Kuen-Feng
author_sort Fan, Li-Ching
collection PubMed
description Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3(Tyr705) suppression in hepatocellular carcinoma. Regorafenib has a closely related chemical structure as sorafenib and is approved for the pharmacotherapy of mCRC. Herein, we evaluate whether regorafenib activates PTPase SHP-1 in the same way as sorafenib to abolish EMT-related invasion/metastasis in CRC. Notably, regorafenib exerted potent anti-EMT activity to curb TGF-β1-induced EMT/invasion in vitro as well inhibited lung metastatic outgrowth of SW480 mesenchymal cells in vivo. Mechanistically, regorafenib-enhanced SHP-1 activity significantly impeded TGF-β1-induced EMT/invasion via low p-STAT3(Tyr705) level as proved by a SHP-1 inhibitor or siRNA-mediated SHP-1 depletion. Conversely, overexpression of SHP-1 further enhanced the inhibitory effects of regorafenib on TGF-β1-induced p-STAT3(Tyr705) and EMT/invasion. Regorafenib directly activates SHP-1 by potently relieving the autoinhibited N-SH2 domain of SHP-1 to inhibit TGF-β1-induced p-STAT3(Tyr705) and EMT/invasion. Importantly, the clinical evidence indicated that SHP-1 was positively correlated with E-cadherin and that significantly determined the overall survival of CRC patients. This result further confirms our in vitro data that SHP-1 is a negative regulatory PTPase in EMT regulation and serves as a pharmacological target for mCRC therapy. Collectively, activating PTPase SHP-1 by regorafenib focusing on its anti-EMT activity might be a useful pharmacotherapy for mCRC.
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spelling pubmed-53254312017-03-23 Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer Fan, Li-Ching Teng, Hao-Wei Shiau, Chung-Wai Tai, Wei-Tien Hung, Man-Hsin Yang, Shung-Haur Jiang, Jeng-Kai Chen, Kuen-Feng Oncotarget Research Paper Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3(Tyr705) suppression in hepatocellular carcinoma. Regorafenib has a closely related chemical structure as sorafenib and is approved for the pharmacotherapy of mCRC. Herein, we evaluate whether regorafenib activates PTPase SHP-1 in the same way as sorafenib to abolish EMT-related invasion/metastasis in CRC. Notably, regorafenib exerted potent anti-EMT activity to curb TGF-β1-induced EMT/invasion in vitro as well inhibited lung metastatic outgrowth of SW480 mesenchymal cells in vivo. Mechanistically, regorafenib-enhanced SHP-1 activity significantly impeded TGF-β1-induced EMT/invasion via low p-STAT3(Tyr705) level as proved by a SHP-1 inhibitor or siRNA-mediated SHP-1 depletion. Conversely, overexpression of SHP-1 further enhanced the inhibitory effects of regorafenib on TGF-β1-induced p-STAT3(Tyr705) and EMT/invasion. Regorafenib directly activates SHP-1 by potently relieving the autoinhibited N-SH2 domain of SHP-1 to inhibit TGF-β1-induced p-STAT3(Tyr705) and EMT/invasion. Importantly, the clinical evidence indicated that SHP-1 was positively correlated with E-cadherin and that significantly determined the overall survival of CRC patients. This result further confirms our in vitro data that SHP-1 is a negative regulatory PTPase in EMT regulation and serves as a pharmacological target for mCRC therapy. Collectively, activating PTPase SHP-1 by regorafenib focusing on its anti-EMT activity might be a useful pharmacotherapy for mCRC. Impact Journals LLC 2016-08-26 /pmc/articles/PMC5325431/ /pubmed/27580057 http://dx.doi.org/10.18632/oncotarget.11636 Text en Copyright: © 2016 Fan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Fan, Li-Ching
Teng, Hao-Wei
Shiau, Chung-Wai
Tai, Wei-Tien
Hung, Man-Hsin
Yang, Shung-Haur
Jiang, Jeng-Kai
Chen, Kuen-Feng
Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title_full Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title_fullStr Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title_full_unstemmed Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title_short Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
title_sort regorafenib (stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325431/
https://www.ncbi.nlm.nih.gov/pubmed/27580057
http://dx.doi.org/10.18632/oncotarget.11636
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